Neuronal substance P drives metastasis through an extracellular RNA-TLR7 axis

• 成果类型: Article
• 署名作者: Padmanaban, Veena; Keller, Isabel; Seltzer, Ethan S.; Ostendorf, Benjamin N.; Kerner, Zachary; Tavazoie, Sohail F.
• 署名单位: Rockefeller University; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Helmholtz Association; Max Delbruck Center for Molecular Medicine; Rockefeller University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4365
• DOI: 10.1038/s41586-024-07767-5
• 发表日期: 2024-09-05
• 页码: 207-+
• 关键词: single-stranded rna; nk-1 receptor; tumor-growth; tnf-alpha; cancer; prostate; ribonuclease; cells; identification; RECOGNITION

摘要

Tumour innervation is associated with worse patient outcomes in multiple cancers(1,2), which suggests that it may regulate metastasis. Here we observed that highly metastatic mouse mammary tumours acquired more innervation than did less-metastatic tumours. This enhanced innervation was driven by expression of the axon-guidance molecule SLIT2 in tumour vasculature. Breast cancer cells induced spontaneous calcium activity in sensory neurons and elicited release of the neuropeptide substance P (SP). Using three-dimensional co-cultures and in vivo models, we found that neuronal SP promoted breast tumour growth, invasion and metastasis. Moreover, patient tumours with elevated SP exhibited enhanced lymph node metastatic spread. SP acted on tumoral tachykinin receptors (TACR1) to drive death of a small population of TACR1(high) cancer cells. Single-stranded RNAs (ssRNAs) released from dying cells acted on neighbouring tumoural Toll-like receptor 7 (TLR7) to non-canonically activate a prometastatic gene expression program. This SP- and ssRNA-induced Tlr7 gene expression signature was associated with reduced breast cancer survival outcomes. Therapeutic targeting of this neuro-cancer axis with the TACR1 antagonist aprepitant, an approved anti-nausea drug, suppressed breast cancer growth and metastasis in multiple models. Our findings reveal that tumour-induced hyperactivation of sensory neurons regulates multiple aspects of metastatic progression in breast cancer through a therapeutically targetable neuropeptide/extracellular ssRNA sensing axis.